Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are important causes of chronic liver disease in the United States. The NASH Clinical Research Network (NASH CRN) was established in 2002 to conduct research related to its clinical features, risk factors, pathogenesis, natural history and treatment in children and adults. The initial funding period of the NASH CRN has been very productive in establishing and conducting network-wide protocols and numerous ancillary and pilot studies. Encouraged by its success, the NIDDK has issued RFA-DK-08-505 whose objective is to continue the NASH CRN for additional five years, The objectives of the NASH CRN during the next funding period are (a) to successfully complete the 3 network-wide studies initiated during the initial funding period. These include the observational longitudinal study of NAFLD in adults and children (NAFLD Database study, n=l,215), a randomized double blind controlled therapeutic study in adult non diabetic patients with NASH (PIVENS, n=247), and a randomized double blind controlled therapeutic study in children with NASH (TONIC, n=173). The NAFLD Database study will be amended to meet additional goals during the next funding period. These modifications may include extending the length of follow-up of those enrolled, consideration of a follow-up liver biopsy in a subset of patients without cirrhosis for better assessment of histological natural history and enrolling carefully chosen controls without NAFLD (b) to successfully complete the ancillary and pilot studies that have been begun during the initial funding period, (c) to conduct additional therapeutic studies in adults and children with NASH since currently available options to treat NASH are limited. Subsets of patients requiring immediate attention include (but not limited) to those with diabetes because of the higher prevalence and greater severity of disease (d) to initiate and complete additional ancillary studies based on extensive clinical material and biosamples collected thus far. In the present funding period, we propose to complete the specific aims stated above and additionally conduct 2 clinical trials using S adenosyl L-methionine and pentoxifylline, based on sound pathophysiological rationale developed during the initial funding period. Public Health Relevance: (provided by the applicant) NAFLD is the commonest liver disease in North America affecting both children and a third of adults. NASH is a severe form of NAFLD and a significant clinical component of the metabolic syndrome. At least 15% of patients with NASH will progress to develop cirrhosis in an estimated 6 milion Americans. The societal and economic costs of this disease burden provide a compelling public health rationale for the proposed studies.